Actinomycin‐D‐resistant in vitro mouse cell line derived from a methylcholanthrene‐induced sarcoma: Decrease of malignancy and antigenic characteristics

Abstract

The tumorigenic EPO clonal cell line, derived from a methylcholanthrene-induced murine sarcoma, was exposed to increasing concentrations of actinomycin D and gave rise to a subline, resistant to 0.02 mug of actinomycin D per ml of medium, which was designated EPO/ADj. Drug resistance was accompained by a striking decrease of tumorigenic capacity as determined by the tumor take incidence and tumor growth rate in syngeneic C57BL/6 mice (normal and X-irradiated), as well as by tumor take incidence in the cheek pouch of cortisone-treated weanling Syrian hamsters. One of the tumors obtained after inoculation of EPO/ADj cells into syngeneic mice was reexplanted in culture and developed as the EPO/ADj/T subline. It was found to be relatively resistant to actinomycin D as compared to the parental EPO cells. The morphology of cells changed with actinomycin-D-resistance: EPO/ADj cells were more spread and flattened and less overlapping than the original fibroblast-like EPO cells. EPO/ADj/T cells, however, had an aspect similar to that of EPO cells. No major differences were seen between the karyotypes of EPO, EPO/ADj and EPO/ADj/T cells. Tumor-specific antigen(s), characteristic of drug-sensitive, parental EPO line, was expressed in the resistant EPO/ADj and EPO/ADj/T lines, as shown by: (a) transplantation resistance to challenge with EPO cells in syngeneic mice pretreated with EPO/ADj cells; and (b) cross-reactivity in indirect immunofluorescence tests performed with sera from syngeneic animals hyperimmunized with EPO or EPO/ADj cells. Furthermore, an additional surface antigen(s), absent from EPO cells, was demonstrated in EPO/ADj and EPO/ADj/T cells by means of immunofluorescence tests performed with specific anti-EPO/ADj syngeneic sera previously absorbed on EPO or EPO/ADj cells.

Intrinsic or acquired drug resistance and metastasis: Are they linked phenotypes?

“…However, there are several reports in the literature which indicate that if anything, cell lines selected in vitro for drug resistance usually manifest a non-tumorigenic phenotype in vivo or are strongly suppressed in their ability to form tumors and/or metastasize [Ganapathi et al, 1987;Giavazzi et al, 1983;Sircar et al, 1987;Kawai et al, 1990;Biedler et al, 1975;Belehradek et al, 19741. Biedler has coined the term "reverse transformation" to describe the phenomenon of reduced malignant aggressiveness expressed by drug-resistant cells [Meyers et al, 19861.…”

Correlation between Characteristics of Transformation and Malignancy of Intra and Interspecific Somatic Hybrid Cells

“…In view of recently published results [7,8,19,20], we critically evaluated the tests we used to define transformation. We showed previously [13] that the hybrid cell lines derived from the common parent, DC-3F/ADX/Aza acquired resist ance to actinomycin-D which is believed to be a dominant characteristic [21,22], These data indicate that the property of an hybrid cell line can be more influenced by one parent cell line. We consider that the property expressed must be the consequence of a chromosome segregation in the hybrid cells.…”

Failure of Actinomycin D Entrapped in Liposomes to Prolong Survival in Renal Cell Adenocarcinoma-Bearing Mice

“…Development of cellular resistance to actinomycin D has been reported in a variety of mammalian cell pop ulations in vitro [11][12][13][14][15][16][17][18][19] and in vivo [20,21]. It was suggested that this phenomenon results from reduced membrane permeability to this drug leading to reduc tion of cellular ability to incorporate actinomycin D [15,17,22,23].…”